ClinVar Miner

Submissions for variant NM_000209.4(PDX1):c.226G>A (p.Asp76Asn) (rs137852783)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000246150 SCV000302992 benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000948405 SCV000518497 likely benign not provided 2021-05-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28323911, 15170499, 15277425, 19515026, 10720084, 24097065, 10545531, 10545530, 26669242)
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV000445407 SCV000537091 benign Monogenic diabetes 2018-10-12 criteria provided, single submitter research ACMG criteria: BS2 (cases=controls in PMID 17592437, 21569088), BS1 (0.4% MAF in gnomAD)= benign; REVEL 0.245 +BP4/4 predictors + PP3/6 predictors: conflicting evidence, not using) OMIM suggests that it is a susceptability factor for T2DM
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000009409 SCV000746931 uncertain significance Type 2 diabetes mellitus 2017-12-18 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000626294 SCV000746953 likely pathogenic Maturity onset diabetes mellitus in young 2017-12-18 criteria provided, single submitter clinical testing
Invitae RCV000948405 SCV001094610 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000948405 SCV001144244 benign not provided 2019-07-16 criteria provided, single submitter clinical testing
OMIM RCV000009409 SCV000029627 risk factor Type 2 diabetes mellitus 1999-11-01 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030077 SCV000052732 not provided Maturity-onset diabetes of the young type 4 2011-08-18 no assertion provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000030077 SCV001423109 benign Maturity-onset diabetes of the young type 4 2020-01-22 no assertion criteria provided curation The p.Asp76Asn variant in PDX1 (sometimes called IPF1) has been reported in at least 32 individuals with Maturity-Onset Diabetes of the Young (PMID: 15277425, 10545531, 10545530, 17592437), and has been identified in 0.4909% (336/68440) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852783). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. However, this variant does not segregate with disease in many families, including sibling pairs (PMID: 10545531, 15277425). This variant has also been reported as a benign variant, likely benign variant, VUS, likely pathogenic variant, and risk factor for diabetes in ClinVar (Variation ID: 8859). In vitro functional studies provide some evidence that the p.Asp76Asn variant may slightly impact protein function, but this evidence is not conclusive (PMID: 10545531). These types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for Maturity-Onset Diabetes of the Young in an autosomal dominant manner based on a higher than expected frequency in control cohorts and nonsegregation with MODY. ACMG/AMP Criteria applied: BS2, BS4, BP4 (Richards 2015).

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